Technical Field
The present disclosure generally relates to N,N-disubstituted amide, carbamate, urea and sulfonamide compounds and to their use as integrin agonists for enhancing binding of integrin-expressing cells to integrin-binding ligands or receptors.
Description of Related Art
Many human diseases are characterized by severe tissue damage which leads to faulty or decreased organ function. Cell-based therapies using stem cells or progenitor cells have shown promise in improving functional outcomes and regenerating tissue. These positive effects appear to be the result of differentiation of the injected cells into the relevant cell type and/or by release of paracrine factors that stimulate restoration of host tissue. The cells usually considered for use in these procedures are embryonic stem cells, adult stem/progenitor cells, or induced pluripotent stem cells. The cells are typically injected intravenously or directly into, or around, the damaged tissue. Regardless of the cell type, mechanism of action, or how they are delivered, it is critical that the cells home to, and are retained in, the relevant injured tissue. Low levels of cell retention observed in animal models and clinical trials are considered one of the major impediments to the progress of cell-based therapy. Even when cells are injected locally, less than 10% of injected cells are typically retained after one hour and this number decreases over time. The retention rates are even lower when delivered systemically. Methods that increase the rate of retention of exogenously delivered cells would greatly further efforts in regenerative medicine.
The process by which cells adhere to tissues is mediated by adhesion molecules expressed on the cell surface. These adhesion molecules bind to their respective ligands on the cells and extracellular matrix that comprise the tissue. One of the predominant classes of adhesion molecules that mediate these interactions are a family of cell surface receptors called integrins. The integrins are heterodimeric proteins comprised of an α and a β subunit. At present, 18 α subunits and 8 β subunits have been identified that combine to form no less than 24 distinct integrin receptor pairs each with its own ligand specificity. Ligands recognized by integrins include extracellular matrix molecules (e.g., fibronectin, vitronectin, laminin, collagen) and members of the immunoglobulin supergene family (e.g., vascular cell adhesion molecule (VCAM)-1, intracellular adhesion molecule (ICAM)-1, mucosal addressin cell adhesion molecule (MAdCAM)-1). As cell adhesion receptors, integrins are not only involved in cellular homing, but also cell migration, proliferation, and survival.
In animal models of ischemic disease, pretreatment of progenitor cells with antibodies or other biologics that can activate integrins have been shown to increase cell incorporation into the relevant tissue and improve neovascularization (Chavakis, E., et al. 2005. Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 201:63-72; and Chavakis, E., A., et al. 2007. High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res 100:204-212). There is continuing interest in integrin-mediated adhesion and in its potential therapeutic applications.